3-aryl-2-isoxazolines as antiinflammatory agents

ABSTRACT

This invention relates to 3-aryl-2-isoxazoline compounds which are selective inhibitors of phosphodiesterase type IV (PDE IV ). The 3-aryl-2-isoxazolines are useful in the treatment of AIDS, asthma, arthritis, bronchitis, chronic obstructive pulmonary disease, psoriasis, allergic rhinitis, dermatitis, shock, atopic dermatitis, rheumatoid arthritis and osteoarthritis. This invention also relates to pharmaceutical compositions useful therefor.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is the national stage of PCT Application No.PCT/IB94/00313 having an international filing date of Oct. 12, 1994,which is a continuation of U.S. application Ser. No. 08/157,241, filedNov. 26, 1993, now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to a series of 3-aryl-2-isoxazoline compoundswhich are selective inhibitors of phosphodiesterase (PDE) type IV and assuch are useful in the treatment of AIDS, asthma, arthritis, bronchitis,chronic obstructive airways disease, psoriasis, allergic rhinitis,dermatitis and other inflammatory diseases.

This invention also relates to the pharmaceutically acceptable salts ofsaid compounds; to a method of using such compounds in inhibitingPDE_(IV), the treatment of inflammatory conditions and the treatment ofAIDS, asthma, arthritis, bronchitis, chronic obstructive airwaysdisease, psoriasis, allergic rhinitis and dermatitis in mammals,especially humans; and to pharmaceutical compositions useful therefor.

The "inflammatory conditions" which can be treated according to thisinvention include, but are not limited to, chronic obstructive pulmonarydisease, septic shock, atopic dermatitis, bronchitis, rheumatoidarthritis and osteoarthritis.

Since the recognition that cyclic AMP is an intracellular secondmessenger (E. W. Sutherland, and T. W. Rall, Pharmacol. Rev., 1960, 12,265), inhibition of the phosphodiesterases has been a target formodulation and, accordingly, therapeutic intervention in a range ofdisease processes. More recently, distinct classes of PDE have beenrecognized (J. A. Beavo and D. H. Reifsnyder, TiPS, 1990, 11, 150), andtheir selective inhibition has led to improved drug therapy (C. D.Nicholson, R. A. Challiss and M. Shahid, TiPS, 1991, 12, 19). Moreparticularly, it has been recognized that inhibition of PDE_(IV) canlead to inhibition of inflammatory mediator release (M. W. Verghese etal., J. Mol. Cell Cardiol., 1989, 12 (Suppl. II), S 61) and airwaysmooth muscle relaxation (T. J. Torphy in Directions for New Anti-AsthmaDrugs, eds S. R. O'Donnell and C. G. A. Persson, 1988, 37,Birkhauser-Verlag). Thus, compounds that inhibit PDE_(IV), but whichhave poor activity against other PDE types, would inhibit the release ofinflammatory mediators and relax airway smooth muscle without causingcardiovascular effects or antiplatelet effects.

Certain isoxazoline phosphonic acid compounds are disclosed to be usefulfor the treatment of diseases of the immune system in U.S. Pat. No.5,006,515.

Certain catechol diethers are disclosed to be useful as PDE_(IV)inhibitors and as such are useful in the treatment of inflammatorydiseases, AIDS, asthma, arthritis, bronchitis, chronic obstructiveairways disease, psoriasis, allergic rhinitis and dermatitis, incopending U.S. patent application, Ser. No. 07/984,408 filed Dec. 2,1992, which application is assigned to the assignee hereof.

Certain pyrimidone compounds have been disclosed to be useful asantidepressants by Saccomano et al., in European Patent Application EPO247 725 A2. The same pyrimidone compounds have been disclosed to beuseful against asthma and certain skin disorders in International PatentApplication No. PCT/US90/02162, published May 30, 1991 as InternationalPublication Number WO 91/07178.

SUMMARY OF THE INVENTION

This invention is concerned with a series of 3-aryl-2-isoxazolinecompounds and to the pharmaceutically acceptable salts of suchcompounds. These new compounds are selective inhibitors of PDE_(IV), andas such are useful in the treatment of inflammatory conditions, AIDS,asthma, arthritis, bronchitis, chronic obstructive airways disease,psoriasis, allergic rhinitis and dermatitis in mammals, especiallyhumans.

The compounds of the present invention are of the formula (I) ##STR1##the racemic, racemic-diastereomeric mixtures and optical isomers of saidcompounds and the pharmaceutically acceptable salts thereof wherein

Y¹ and Y² are independently selected from the group consisting ofhydrogen, (C₁ -C₆)alkyl, optionally substituted phenylalkyl having 1 to6 carbons in the alkyl portion, optionally substituted phenoxyalkylhaving 1 to 6 carbons in the alkyl portion, (C₃ -C₇)cycloalkyl, fluoro,chloro, bromo, iodo, --OR¹ and --OR² ;

wherein the aromatic portion of the optionally substituted phenylalkyl,and the aromatic portion of the optionally substituted phenoxyalkyl areoptionally independently substituted with (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy,halogen or CF₃ ;

R¹ is alkyl having 1 to 3 carbons, fluoromethyl, difluoromethyl ortrifluoromethyl;

R² is (C₁ -C₃)alkyl, (C₃ -C₇)cycloalkyl, alkoxyalkyl having 3 to 7carbons in the alkoxy portion and 2 to 4 carbons in the alkyl portion,optionally substituted phenoxyalkyl having 2 to 6 carbons in the alkylportion, optionally substituted phenylalkyl having 1 to 6 carbons in thealkyl portion, bicycloalkyl having 6 to 9 carbons or optionallysubstituted indanyl;

wherein the aromatic portion of the optionally substituted phenylalkyl,the aromatic portion of the optionally substituted phenoxyalkyl and theoptionally substituted indanyl are optionally independently substitutedwith (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, halogen or CF₃ ;

R³ is hydrogen, (C₁ -C₃)alkyl, mono-hydroxyalkyl having 1 to 3 carbonsor alkoxyalkyl having 1 to 3 carbons in the alkyl portion and 1 to 3carbons in the alkoxy portion;

R⁴ is hydrogen, (C₁ -C₅)alkyl, --COOH, alkoxyalkyl having 1 to 3 carbonsin the alkyl portion and 1 to 3 carbons in the alkoxy portion,N-alkylaminoalkyl having 1 to 3 carbons in the alkylamino portion and 1to 3 carbons in the alkyl portion or N,N-dialkylaminoalkyl having atotal of 2 to 6 carbons in the dialkylamino portion and 1 to 3 carbonsin the alkyl portion;

or R³ and R⁴ are taken together with the carbon atoms to which they areattached and form --CH₂ OCH₂ OCH₂ --; and

R⁵ is hydrogen, --CHO, amino, aminoalkyl having 1 to 3 carbons, ##STR2##mono-hydroxyalkyl having 1 to 3 carbons, --(CH₂)_(b) --COOR⁶, --COR⁷,--(CH₂)_(m) CO₂ H, (C₁ -C₄)alkyl, hydroxy, --(CH₂)_(q) CONX² X³,--(CH₂)_(r) SO₂ NX⁴ X⁵, --(CH₂)_(s) PO₃ H₂ or ##STR3## wherein b is 0 oran integer from 1 to 6; m, n, q, r, s and t are independently 0, 1, 2, 3or 4;

R⁶ and R⁷ are each independently (C₁ -C₄)alkyl;

X¹ is hydrogen, (C₁ -C₄)alkyl, --O(C₁ -C₄)alkyl or alkoxyphenyl havingone to four carbon atoms in the alkoxy portion;

X², X³, X⁴ and X⁵ are each independently hydrogen or (C₁ -C₃)alkyl; and

X⁶ is (C₁ -C₃)alkyl or phenyl;

provided that when R¹ is (C₁ -C₃)alkyl, R² is (C₁ -C₃)alkyl, R³ ishydrogen, and R⁴ is hydrogen then R⁵ is not --(CH₂)_(s) PO₃ H₂ ; and

when R⁴ is --COOH then R⁵ is not --COOH; and that

both Y¹ and Y² cannot be hydrogen at the same time.

A preferred group of compounds or the pharmaceutically acceptable saltsthereof of this invention are those compounds of the formula (I) whereinY¹ is --OR¹ and is attached to the 4-position of the phenyl ring and Y²is --OR² and is attached to the 3-position of the phenyl ring.

A more preferred group of compounds or the pharmaceutically acceptablesalts thereof of this invention are those compounds of the formula (I)wherein Y¹ is --OR¹ and is attached to the 4-position of the phenyl ringand Y² is --OR² and is attached to the 3-position of the phenyl ring,wherein R¹ is methyl; R² is (C₃ -C₇)cycloalkyl, bicycloalkyl having 6 to9 carbons, or phenylalkyl having 1 to 6 carbons in the alkyl portion; R³is hydrogen or (C₁ -C₃)alkyl; R⁴ is hydrogen or (C₁ -C₅)alkyl; and R⁵ is--(CH₂)_(m) CO₂ H, --CHO, --COCH₃, amino, hydroxy, mono-hydroxyalkylhaving 1 to 3 carbons, aminoalkyl having 1 to 3 carbons, or ##STR4##wherein X¹ is (C₁ -C₄)alkyl or alkoxyphenyl having one to four carbonatoms in the alkoxy portion and n is 0 or an integer from 1 to 3.

Another more preferred group of compounds or the pharmaceuticallyacceptable salts thereof are those compounds of the formula (I) whereinY¹ is --OR¹ and is attached to the 4-position of the phenyl ring and Y²is --OR² and is attached to the 3-position of the phenyl ring, whereinR¹ is methyl; R² is 5-phenylpentyl; R³ is hydrogen; R⁴ is hydrogen orCH₃ and R⁵ is --(CH₂)_(s) PO₃ H₂ wherein s is 0 or 1.

Further, another more preferred group of compounds or thepharmaceutically acceptable salts thereof are those compounds of theformula (I) wherein Y¹ is --OR¹ and is attached to the 4-position of thephenyl ring and Y² is --OR² and is attached to the 3-position of thephenyl ring, wherein R¹ is methyl; R² is cyclopentyl; R³ is hydrogen; R⁴is hydrogen and R⁵ is --(CH₂)_(s) PO₃ H₂ wherein s is 0.

Furtherstill, another more preferred group of compounds or thepharmaceutically acceptable salts thereof are those compounds of theformula (I) wherein Y¹ is --OR¹ and is attached to the 4-position of thephenyl ring and Y² is --OR² and is attached to the 3-position of thephenyl ring, wherein R¹ is methyl, R² is 4-phenylbutyl, 5-phenylpentylor cyclopentyl, R³ is hydrogen or (C₁ -C₃)alkyl; R⁴ is hydrogen or (C₁-C₅)alkyl; and R⁵ is --(CH₂)_(m) CO₂ H,

--CHO, --COOH₃, amino, hydroxy, mono-hydroxyalkyl having 1 to 3 carbons,aminoalkyl having 1 to 3 carbons, or ##STR5## wherein X¹ is (C₁-C₄)alkyl or alkoxyphenyl having one to four carbon atoms in the alkoxyportion and n is 0 or an integer from 1 to 3.

Yet another more preferred group of compounds or the pharmaceuticallyacceptable salts thereof are those compounds of the formula (I) whereinY¹ is --OR¹ and is attached to the 4-position of the phenyl ring and Y²is --OR² and is attached to the 3-position of the phenyl ring, whereinR¹ is methyl; R² is 5-phenylpentyl; R³ is hydrogen or (C₁ -C₃)alkyl; R⁴is hydrogen or (C₁ -C₅)alkyl and R⁵ is --(CH₂)_(m) CO₂ H, --CHO,--COCH₃, amino, hydroxy, mono-hydroxyalkyl having 1 to 3 carbons,aminoalkyl having 1 to 3 carbons, or ##STR6## wherein X¹ is (C₁-C₄)alkyl or alkoxyphenyl having one to four carbon atoms in the alkoxyportion and n is 0 or an integer from 1 to 3.

Yet still another more preferred group of compounds or thepharmaceutically acceptable salts thereof are those compounds of theformula (I) wherein Y¹ is --OR¹ and is attached to the 4-position of thephenyl ring and Y² is --OR² and is attached to the 3-position of thephenyl ring, wherein R¹ is methyl; R² is 5-phenylpentyl; R³ is hydrogenor (C₁ -C₃)alkyl; R⁴ is hydrogen or (C₁ -C₅)alkyl and R⁵ is --(CH₂)_(m)CO₂ H, --CHO, --COCH₃, hydroxy or mono-hydroxyalkyl having 1 to 3carbons.

A most preferred group of compounds or the pharmaceutically acceptablesalts thereof are those compounds of the formula (I) wherein Y¹ is --OR¹and is attached to the 4-position of the phenyl ring and Y² is --OR² andis attached to the 3-position of the phenyl ring, wherein R¹ is methyl;R² is 5-phenylpentyl; R³ is hydrogen or (C₁ -C₃)alkyl; R⁴ is hydrogen or(C₁ -C₅)alkyl and R⁵ is --(CH₂)_(m) CO₂ H.

Yet still another most preferred group of compounds or thepharmaceutically acceptable salts thereof are those compounds of theformula (I) wherein Y¹ is --OR¹ and is attached to the 4-position of thephenyl ring and Y² is --OR² and is attached to the 3-position of thephenyl ring, wherein R¹ is methyl; R² is 5-phenylpentyl; R³ is hydrogen;R⁴ is hydrogen or (C₁ -C₅)alkyl and R⁵ is --(CH₂)_(m) CO₂ H wherein m=0.

A particularly preferred group of compounds or the pharmaceuticallyacceptable salts thereof are those compounds of the formula (I) whereinY¹ is --OR¹ and is attached to the 4-position of the phenyl ring and Y²is --OR² and is attached to the 3-position of the phenyl ring, whereinR¹ is methyl; R² is 5-phenylpentyl; R³ is hydrogen; R⁴ is hydrogen,methyl, ethyl or propyl and R⁵ is --(CH₂)_(m) CO₂ H wherein m=0.

Most particularly preferred compounds of this invention are (+) or(-)-5-ethyl-3-4-methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazoline-5-carboxylic acid.Of the two, (-)-5-ethyl-3-4-methoxy-3-(5-phenylpentyloxy)!-phenyl-2-isoxazoline-5-carboxylic acidis the more preferred compound.

The term alkyl encompasses both straight and branched chains. Thearomatic portion of the optionally substituted phenylalkyl, the aromaticportion of the optionally substituted phenoxyalkyl and the optionallysubstituted indanyl may be substituted by one or more substituents.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention having the formula (I) arecomprised of the racemic, racemic-diastereomeric mixtures and opticalisomers of said compounds and the pharmaceutically acceptable saltsthereof. The compounds of the present invention, having the formula I asdefined above, are readily and generally prepared by the followingreaction processes.

Compounds of the formula (I) wherein R⁵ is a carboxylic acid can besynthesized by mixing a methanol solution of the corresponding alkylester, wherein R⁵ is ethyl ester, with an aqueous solution of aninorganic base such as KOH. The mixture is stirred at room temperatureuntil the reaction is substantially complete. The reaction mixture isworked-up according to methods well-known to those skilled in the art.

Compounds of the formula (I) wherein R⁵ is carboxymethyl (--CH₂ CO₂ H)are synthesized by reacting a compound of the formula (I) wherein R⁵ ishydroxymethyl (--CH₂ OH) with p-toluenesulfonyl chloride in the presenceof a tertiary amine such as triethylamine in an inert solvent at 0° C.to 50° C. to give a compound of the formula (I) wherein R⁵ is --CH₂ OTs,which is reacted with lithium, sodium or potassium cyanide in an inertsolvent such as DMSO at 0° C. to 100° C. to give a compound of theformula (I) wherein R⁵ is --CH₂ CN, which is hydrolyzed with aninorganic base such as KOH in water and an alcoholic solvent at roomtemperature to 100° C.

The compounds of formula (I) wherein R⁵ is an aldehyde can besynthesized by dissolving the corresponding compound of formula (I)wherein R⁵ is --CONH-alkyl in a dry inert solvent such astetrahydrofuran, decreasing the temperature of the solution to between-65° to -78° C. and then adding dropwise 3 to 5 equivalents ofdiisobutylaluminum hydride (DIBAL-H) in hexane. The reaction mixture ismaintained at about -78° C. for about 30 to 60 minutes and then allowedto warm to room temperature. The reaction mixture is worked-up accordingto methods well known to those skilled in the art. The resultingaldehyde compound can be optionally reduced to obtain the correspondingalcohol. The aldehyde compound is dissolved in an alcoholic solvent andtreated with sodium borohydride; the mixture is stirred at roomtemperature until the reaction is substantially complete.

Compounds of the formula (I) wherein R⁵ is hydroxy can be synthesized bydissolving the corresponding acyloxy derivative, such as when R⁵ is--OCOCH₃, in an alcoholic solvent and treating the solution withapproximately 1.1 equivalents of sodium methoxide. The reaction mixtureis stirred at room temperature until the reaction is substantiallycomplete, which is usually about 1 hour.

Compounds of the formula (I) wherein R⁵ is a mono-hydroxyalkyl, aresynthesized by reducing the corresponding ester, wherein R⁵ is an alkylester, with diisobutylaluminum hydride (DIBAL-H) according to thefollowing procedure. A compound of formula (I) wherein R⁵ is a methyl orethyl ester, is dissolved in THF and chilled to about -78° C.Approximately 2 to 4 equivalents of DIBAL-H in hexane is added to thecold THF mixture. The solution is warmed to about -30° C. and thenquenched with a dilute solution of HCl.

Alternatively, the compounds of formula (I) wherein R⁵ is hydroxymethyl,are synthesized by reducing a compound of formula (I) wherein R⁵ is analdehyde. The aldehyde compound is dissolved in an alcoholic solvent andtreated with sodium borohydride; the mixture is stirred at roomtemperature until the reaction is substantially complete. Further, thecompounds of formula (I) wherein R⁵ is a 1-hydroxyalkyl (i.e.,--CO(OH)alkyl) are synthesized by reducing a corresponding compound offormula (I) wherein R⁵ is a ketone moiety (i.e., --COalkyl) according tothe following procedure. The ketone compound of formula (I) is dissolvedin an alcoholic solvent and cooled to about 0° C., to which is addedsodium borohydride. The mixture is stirred until the bubbling ceases andthen stirred at room temperature for approximately 1 hour.

Certain compounds of the formula (I) are synthesized according to thefollowing procedure. To a mixture of N-chlorosuccinimide and pyridine inan inert solvent, such as methylene chloride, is added an oxime of theformula ##STR7## wherein Y¹ and Y² are as defined above for formula (I).The mixture is allowed to stir for about 2 to 5 hours, preferably about2 hours. A compound of the formula ##STR8## wherein R³, R⁴ and R⁵ are asdefined above for formula I, is added followed by the addition oftriethylamine to the mixture and the mixture stirred for about 2 hoursmore at room temperature. The reaction is worked up according to methodswell known to those skilled in the art.

Compounds of the formula (I) wherein R⁵ is aminomethyl are synthesizedaccording to the following procedure. A compound of the formula ##STR9##wherein Y¹, Y², R³ and R⁴ are as defined above for formula (I), isdissolved in a mixture of methanol and water. An inorganic base such asKOH is added to the mixture and the reaction mixture is allowed to stirat room temperature for about 12 to 24 hours, preferably 16 hours. Thereaction is worked-up according to methods well-known to those skilledin the art.

Compounds of the formula (I) wherein R⁴ is --COOH and R⁵ is an aminogroup are synthesized according to the following procedure. A compoundof the formula ##STR10## wherein Y¹, Y² and R³ are as defined above forformula (I), is reacted with bromotrimethylsilane for about 12 to 24hours, preferably 16 hours. Acetonitrile is added, for solubility ifnecessary, to the reaction mixture and the mixture is heated to refluxuntil the reaction is substantially complete. The reaction is worked-upaccording to methods well-known to those skilled in the art.

Compounds of formula (I) wherein R⁵ is --(CH₂)_(s) PO₃ H₂ aresynthesized according to the following procedure. A solution of theappropriate phosphonate dissolved in trimethylsilylbromide is stirredfor about 2 hours at room temperature. The mixture is evaporated and theresidue is diluted with H₂ O and an organic solvent such as CH₂ Cl₂ andstirred for about 2 hours. The mixture is filtered and the aqueous layeris basified with an aqueous inorganic base such as 1N NaOH. The organiclayer is discarded and the aqueous layer is washed with additionalorganic solvent such as CH₂ Cl₂. The aqueous layer is acidified andextracted with an organic solvent such as EtOAc. Evaporating the EtOAcyields the desired compound.

The synthetic methods outlined above together with the followingexamples describe methods which were and can be employed to prepare thecompounds of this invention.

As ascertained by one skilled in the art enabled by this disclosure,pharmaceutically-acceptable acid addition salts of certain compounds ofthis invention include, but are not limited to, those formed with HCl,HBr, HNO₃, H₂ SO₄, H₃ PO₄, CH₃ SO₃ H, p--CH₃ C₆ H₄ SO₃ H, CH₃ CO₂ H,gluconic acid, tartaric acid, maleic acid and succinic acid. In the caseof those compounds of the formula (I) which contain a further basicnitrogen, it will, of course, be possible to form diacid addition salts(e.g., the dihydrochloride) as well as the usual monoacid addition salt.As ascertained by one skilled in the art enabled by this disclosure,pharmaceutically-acceptable cationic salts of certain compounds of thisinvention include, but are not limited to, those of sodium, potassium,calcium, magnesium, ammonium, N,N'-dibenzylethylenediamine,N-methylglucamine (meglumine), ethanolamine and diethanolamine.

The starting materials and reagents required for the synthesis of thecompounds of the present invention are readily available, eithercommercially, according to literature methods, or by methods exemplifiedin Preparations below.

The ability of the compounds or the pharmaceutically acceptable saltsthereof to inhibit PDE_(IV) and, consequently, demonstrate theireffectiveness for treating inflammatory diseases is shown by thefollowing in vitro assay.

BIOLOGICAL ASSAY (Human Lung PDE_(IV))

Thirty to forty grams of human lung tissue is placed in 50 ml of pH 7.4Tris/phenylmethylsulfonyl fluoride (PMSF)/sucrose buffer and homogenizedusing a Tekmar Tissumizer® (Tekmar Co., 7143 Kemper Road, Cincinnati,Ohio 45249) at full speed for 30 seconds. The homogenate is centrifugedat 48,000×g for 70 minutes at 4° C. The supernatant is filtered twicethrough a 0.22 μm filter and applied to a Mono-Q FPLC column (PharmaciaLKB Biotechnology, 800 Centennial Avenue, Piscataway, N.J. 08854)pre-equilibrated with pH 7.4 Tris/PMSF buffer. A flow rate of 1ml/minute is used to apply the sample to the column, followed by a 2ml/minute flow rate for subsequent washing and elution. Sample is elutedusing an increasing, step-wise NaCl gradient in the Ph 7.4 Tris/PMSFbuffer. Eight ml fractions are collected. Fractions are assayed forspecific PDE_(IV) activity, determined by ³ H!cAMP hydrolysis and theability of a known PDE_(IV) inhibitor (e.g. rolipram) to inhibit thathydrolysis. Appropriate fractions are pooled, diluted with ethyleneglycol (2 ml ethylene glycol/5 ml of enzyme prep) and stored at -20° C.until use.

Compounds are dissolved in DMSO at a concentration of 10 mM and diluted1:25 in water (400 μM compound, 4% DMSO). Further serial dilutions aremade in 4% DMSO to achieve desired concentrations. Final DMSOconcentration in the assay tube is 1%. In duplicate the following areadded, in order, to a 12×75 mm glass tube (all concentrations are givenas final concentrations in assay tube).

i) 25 μl compound or DMSO (1%, for control and blank)

ii) 25 μl pH 7.5 Tris buffer

iii) ³ H!cAMP (1 μM)

iv) 25 μl PDE_(IV) enzyme (for blank, enzyme is preincubated in boilingwater for 5 minutes)

The reaction tubes are shaken and placed in a water bath (37° C.) for 20minutes, at which time the reaction is stopped by placing the tubes in aboiling water bath for 4 minutes. Washing buffer (0.5 ml, 0.1M4-(2-hydroxyethyl)-1-piperazineethanesulfonic acid (HEPES)/0.1M NaCl, pH8.5) is added to each tube on an ice bath. The contents of each tube areapplied to an Affi-Gel 601 column (Biorad Laboratories, P.O. Box 1229,85A Marcus Drive, Melville, N.Y. 11747) (boronate affinity gel, 1 ml bedvolume) previously equilibrated with washing buffer. ³ H!cAMP is washedwith 2×6 ml washing buffer, and ³ H!5'AMP is then eluted with 4 ml of0.25M acetic acid. After vortexing, 1 ml of the elution is added to 3 mlof scintillation fluid in a suitable vial, vortexed and counted for ³H!.

% Inhibition is determined by the formula: ##EQU1## IC₅₀ is defined asthat concentration of compound which inhibits 50% of specific hydrolysisof ³ H!cAMP to ³ H!5'AMP.

For administration to humans to inhibit PDE_(IV) in the treatment ofinflammatory conditions, AIDS, asthma, arthritis, bronchitis, chronicobstructive airways disease, psoriasis, allergic rhinitis, dermatitisand other inflammatory diseases, oral dosages of the compounds aregenerally in the range of from 0.1-500 mg daily for an average adultpatient (70 kg). Thus for a typical adult patient, individual tablets orcapsules contain from 0.1 to 50 mg of active compound, in a suitablepharmaceutically acceptable vehicle or carrier. Tablets or capsules canbe given in multiple dosages to meet the dosage requirement. Dosages forintravenous administration are typically within the range of 0.1 to 10mg per single dose as required. For intranasal or inhaleradministration, the dosage is generally formulated as a 0.1 to 1% (w/v)solution. In practice the physician will determine the actual dosagewhich will be most suitable for an individual patient and it will varywith the age, weight and response of the particular patient. The abovedosages are exemplary of the average case but there can, of course, beindividual instances where higher or lower dosage ranges are merited,and all such dosages are within the scope of this invention.

For human use, the compounds of the formula (I) can be administeredalone, but will generally be administered in an admixture with apharmaceutical diluent or carrier selected with regard to the intendedroute of administration and standard pharmaceutical practice. Forexample, they may be administered orally in the form of tabletscontaining such excipients as starch or lactose, or in capsules orovales either alone or in admixture with excipients, or in the form ofelixirs or suspensions containing flavoring or coloring agents. They maybe injected parenterally; for example, intravenously, intramuscularly orsubcutaneously. For parenteral administration, they are best used in theform of a sterile aqueous solution which may contain other substances;for example, enough salts or glucose to make the solution isotonic. Fortopical administration, they are best used in the form of solutions,lotions, ointments, salves and the like.

Thus in a further aspect the invention provides pharmaceuticalcompositions comprising a compound of the formula (I), orpharmaceutically acceptable salts thereof, together with apharmaceutically acceptable diluent or carrier.

This invention provides a method of inhibiting PDE_(IV) in a mammal inneed thereof which method comprises administering to said mammal aneffective amount of a compound of the formula (I) or a pharmaceuticallyacceptable salt thereof.

This invention further provides a method of treating an inflammatorycondition in a mammal in need thereof which comprises administering tosaid mammal an antiinflammatory amount of a compound of the formula (I)or a pharmaceutically acceptable salt thereof.

Further still, this invention provides a method of treating AIDS,asthma, arthritis, bronchitis, chronic obstructive pulmonary disease,psoriasis, allergic rhinitis, dermatitis or shock in a mammal in needthereof which comprises administering to said mammal an effective amountof a compound or a pharmaceutically acceptable salt thereof.

The present invention is illustrated by the following examples, but itis not limited to the details thereof.

EXAMPLE 1 3-4-Methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazoline-5-carboxylic Acid

To a mixture of 1.00 g (2.43 mmol) of the compound of Preparation 15, 15ml of MeOH, and 5 ml of water was added 273 mg (4.86 mmol) of KOH. Themixture was stirred overnight at RT and was then partially evaporated toremove MeOH. The residue was diluted with water to a volume of 125 ml,acidified with 6N HCl solution, and extracted with EtOAc (2×125 ml). Thecombined extracts were dried (Na₂ SO₄) and evaporated to give 729 mg(78%) of the title compound as an oil. ¹ H NMR (CDCl₃): δ 1.44-1.94 (6H,m), 2.64 (2H, t), 3.66-3.70 (2H, m), 3.89 (3H, s), 4.02 (2H, q, J=7),5.18 (1H, t, J=10), 6.83 (1H, d, J=8), 7.02 (1H, dd, J=8, 2), 7.11-7.31(6 H, m). FABMS (m/e): 384 (M⁺ +1).

EXAMPLES 2-5

The following compounds were prepared substantially according to theprocedure of Example 1.

    __________________________________________________________________________     ##STR11##                                                                    Example                                                                            Ester  R.sup.4                                                                          R.sup.3                                                                          M.P. °C.                                                                    Data                                                   __________________________________________________________________________    2    Compound of                                                                          Me H  101-103                                                                            .sup.1 H NMR(CDCl.sub.3): δ 1.40-1.88(6H,             Preparation 16    m), 1.72(3H, s), 2.58(2H, t, J=7),                                            3.23(1H, d, J=16), 3.78(1H, d,                                                J=16), 3.93(3H, s), 3.96(2H, q,                                               J=7), 6.76(1H, d, J=8), 6.93(1H,                                              dd, J=8, 2), 7.06-7.22(6H, m)                          3    Compound of                                                                          H  Me.sup.a                                                                         101-104                                                                            .sup.1 H NMR(CDCl.sub.3): δ 1.41(3H, d,               Preparation 17    J=7), 1.40-1.88(6H, m), 3.94(3H,                                              s), 3.96-4.01(1H, m), 3.99(2H, q,                                             J=7), 5.00-5.07(1H, m), 6.78(1H,                                              d, J=8), 7.04(1H, d, J=8), 7.10-                                              7.24(6H, m), 7.34(1H, s).                                                     FABMS (m/e): 398(M.sup.+  + 1)                         4    Compound of                                                                          Et H   138-140.sup.b                                                                     Anal. Calc'd for C.sub.24 H.sub.29 NO.sub.5 : C,            Preparation 18    70.05; H, 7.10; N, 3.40. Found:                                               C, 70.11; H, 7.21; N, 3.42                             5    Compound of                                                                          Pr H  153-155                                                                            Anal. Calc'd for C.sub.25 H.sub.31 NO.sub.5 : C,            Preparation 19    70.56; H, 7.34; N, 3.29. Found:                                               C, 70.49; H, 7.39; N, 3.33                             __________________________________________________________________________     .sup.a trans stereochemistry                                                  .sup.b recrystallized from EtOAc                                         

EXAMPLE 6 (+)-5-Ethyl-3-4-methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazoline-5-carboxylic Acid

A mixture of 1.03 g (2.5 mmol) of the compound of Example 4 and 303 mg(2.5 mmol) of (R)-(+)-α-methylbenzylamine were dissolved in 50 ml ofMeOH and the solvent was removed. The residual oil crystallized onstanding in the refrigerator overnight and was triturated in ether. Thesolid, 1.17 g, was recrystallized four times from EtOAc to give 340 mgof a fluffy white solid, mp 144°-145° C.; α!_(D) +26.3° (MeOH). The saltwas partitioned between 20 ml of aqueous 1N HCl solution and 40 ml ofEtOAc. The organic layer was washed with additional aqueous 1N HClsolution (2×20 ml), dried (MgSO₄), and evaporated to 234 mg of a solid.Recrystallization from hexane-EtOAc provided 192 mg of the titlecompound, mp 122°-124°, α!_(D) +30.7° (CHCl₃). Calc'd. for C₂₄ H₂₉ NO₅ :C, 70.05; H, 7.10; N. 3.48. Found: C, 70.12; H, 6.80; N, 3.32.

EXAMPLE 7 (-)-5-Ethyl-3-4-methoxy-3-(phenylpentyloxy)!phenyl-2-isoxazoline-5-carboxylic Acid

All the mother liquors derived from the (R)-α-methylbenzylamine saltdescribed in Example 6 were combined, concentrated, and partitionedbetween EtOAc (100 ml) and aqueous 1N HCl solution (50 ml). The organiclayer was separated, washed with additional aqueous 1N HCl solution(2×50 ml), dried (MgSO₄), and evaporated to 722 mg (1.75 mmol) of asolid. The solid and 212 mg (1.75 mmol) of (S)-(-)-α-methylbenzylaminewere dissolved in 30 ml of EtOAc and crystallization was induced byscratching with a glass rod to yield 605 mg of salt. Tworecrystallizations from EtOAc gave 483 mg of pure salt, mp 145°-146° C.;α!_(D) -26.3° (MeOH). The salt was neutralized as described in Example 6to provide 334 mg of the title compound, mp 122°-123° C. α!_(D) -31.0°(CHCl₃). Calc'd. for C₂₄ H₂₉ NO₅ : C, 70.05; H 7.10; N, 3.48. Found: C,70.02; H, 6.85; N, 3.36.

EXAMPLE 8 (-)-3-4-Methoxy-3-(5-phenylpentyloxy)!phenyl-5-methyl-2-isoxazoline-5-carboxaldehyde

To a solution of 290 mg (0.579 mmol) of the compound of Preparation 22in 20 ml of dry THF at about -78° C. was added dropwise 1.74 ml (1.74mmol) of a solution of 1M diisobutylaluminum hydride in hexane at such arate that the reaction temperature was maintained below about -65° C.After about 20 min of stirring the reaction was allowed to warm to RTwhere TLC analysis indicated the presence of starting material. Themixture was recooled to about -78° C., treated with an additional 0.580ml of 1M diisobutylaluminum hydride solution, and then allowed to warmto RT. A solution (6 ml) of 1N aqueous HCl was added and the organiclayer was extracted with EtOAc (2×50 ml). The combined extracts weredried (MgSO₄) and evaporated to 246 mg of a yellow oil. Purification byflash chromatography using a EtOAc-hexane (1:1) eluant gave 137 mg ofthe title compound as an oil. ¹ H NMR (CDCl₃): δ1.28-1.93 (6H, m), 1.58(3H, s), 2.63 (2H, t, J=7), 3.06 (1H, d, J=16), 3.66 (1H, d, J=16), 3.90(3H, s), 4.03 (2H, t, J=7), 6.83 (1H, d, J=8), 7.00 (1H, d, J=8),7.15-7.31 (6H, m) 9.65 (1H, s); MS (m/e): 382 (M⁺ +1), 352; α!_(D)-35.1° (CHCl₃).

EXAMPLES 9-11

The following compounds were prepared substantially according to theprocedure of Example 8 substituting the indicated amide for that ofProcedure 22.

    __________________________________________________________________________     ##STR12##                                                                    Example                                                                            Amide                                                                              R.sup.4                                                                          M.P. °C.                                                                     α!.sub.D (CHCl.sub.3)                                                         Data                                                 __________________________________________________________________________    9    Cmpd of                                                                            Me oil  +36.6°                                                                        MS(m/e): 382(M.sup.+  + 1), 352                           Prep. 24                                                                 10   Cmpd of                                                                            Pr oil  -29.4°                                                                        .sup.1 H NMR(CDCl.sub.3): δ 0.96(3H,                Prep. 28            t), 1.39-1.93(10H, m), 2.62                                                   (2H, t, J=8), 3.06(1H, d,                                                     J=17), 3.59(1H, d, J=17),                                                     3.86(3H, s), 4.00(3H, t, J=7),                                                6.83(1H, d, J=8), 7.07(1H,                                                    dd, J=8, 2), 7.23-7.30(6H, m),                                                9.67(1H, s)                                          11   Cmpd of                                                                            Pr oil  +37.1°                                                                        MS(m/e): 410(M.sup.+  + 1), 382                           Prep. 27                                                                 __________________________________________________________________________

EXAMPLE 12 5-Hydroxy-3-4-methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazoline

To a solution of 500 mg (1.26 mmol) of the compound of Preparation 29 in15 ml of MeOH was added 0.50 ml (1.50 mmol) of 3M NaOMe solution inMeOH. After stirring for about 1 hr at RT, the mixture was evaporatedand the residue was diluted with 10 ml of ice water. The mixture wasacidified with aqueous 6M HCl solution, extracted with EtOAc (2×50 ml),washed with brine (50 ml), dried (Na₂ SO₄), and evaporated to 307 mg ofan oil. Purification by flash chromatography using a EtOAc-hexane (1:1)eluant afforded 307 mg of the title compound, mp 89°-91° C. Anal.Calc'd. for C₂₀ H₂₅ NO₄ : C, 70.96; H, 7.09; N, 3.93. Found: C, 70.86;H, 7.10; N, 3.97.

EXAMPLE 13 (+)-5-Hydroxymethyl-3-4-methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazoline

To a solution of 300 mg (0.617) of the compound of Preparation 20 in 10ml of dry THF chilled to about -78° C. was added dropwise 1.85 ml (1.85mmol) of 1M diisobutylaluminum hydride solution in hexane. Afterstirring for 20 min at about -78° C., the mixture was allowed to warm toabout -20° C. and was quenched with 4 ml of aqueous 1N HCl solution. Themixture was concentrated, dissolved in 30 ml of EtOAc, washed with water(2×30 ml), dried (MgSO₄), and evaporated to 200 mg of a brown oil.

A solution of 184 mg of the oil above in 3 ml of MeOH was treated with19 mg (0.50 mmol) of sodium borohydride, and the mixture was allowed tostir at RT for about 16 h. The mixture was quenched with aqueous 1N HClsolution and was partially evaporated to remove MeOH. The residue wasextracted with EtOAc (1×50 ml) and the organic layer was separated,washed with water, dried (MgSO₄), and evaporated to a brown oil.Purification by flash chromatography (10 g of silica gel) using aEtOAc-hexane (2:3) eluant afford 96 mg of the title compound as an oil.¹ H NMR (CDCl₃): δ 1.46-1.92 (6H, m), 2.62 (3H, t, J=8), 3.18-3.39 (2H,m), 3.63-3.90 (2H, m), 3.86 (3H, s), 4.80-4.85 (1H, m), 6.83 (1H, d,J=8), 7.02 (1H, dd, J=8, 2), 7.12-7.33 (6H, m), MS (m/e): 370 (M⁺ +1).α!_(D) +58.0° (CHCl₃).

EXAMPLE 14 (-)-5-Hydroxymethyl-3-4-methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazoline

The title compound was prepared substantially according to the procedureof Example 13 substituting the compound of Preparation 21 for thecompound of Preparation 20. α!_(D) -60.0° (CHCl₃).

EXAMPLE 15 (+)-5-Hydroxymethyl-3-4-methoxy-3-(5-phenylpentyloxy)!phenyl-5-methyl-2-isoxazoline

A solution of 200 mg (0.524 mmol) of the compound of Example 9 in 4 mlof MeOH was treated with 18 mg (0.524 mmol) of sodium borohydride andthe mixture was stirred for about 16 h at RT. The mixture was quenchedwith aqueous 1N HCl solution and was partially evaporated to removeMeOH. The residue was diluted with 50 ml of water, extracted with EtOAc(2×50 ml), dried (MgSO₄), and evaporated to 194 mg of an oil.Crystallization of the oil from hexane-ether (3:1) afforded 131 mg ofthe title compound, mp 76°-78° C. α!_(D) +34.7° (CHCl₃). Anal. Calc'dfor C₂₃ H₂₉ NO ₄ 1/4H₂ O: C, 71.14; H, 7.60; N. 3.61. Found: C, 71.51;H, 7.72; N, 3.71.

EXAMPLE 16 (-)-5-Hydroxymethyl-3-4-methoxy-3-(5-phenylpentyloxy)!phenyl-5-methyl-2-isoxazoline

The title compound was prepared substantially according to the procedureof Example 15 substituting the compound of Example 8 for the compound ofExample 9, mp 86°-88° C. α!_(D) -38.2° (CHCl₃). Anal. Calc'd. for C₂₃H₂₉ NO₄ 1/4H₂ O: C, 71.14; H, 7.60; N. 3.61. Found: C, 71.51; H, 7.72;N, 3.71.

EXAMPLE 17 (+/-)-5-Hydroxymethyl-3-4-methoxy-3-(5-phenylpenytyloxy)!phenyl-5-methyl-2-isoxazoline

To a solution of 200 mg (0.47 mmol) of the compound of Preparation 16 in5 ml of THF chilled to about -78° C. was added dropwise 1.03 ml (1.03mmol) of 1.0M diisobutylaluminum hydride solution in hexane. The mixturewas allowed to warm to about 0° C. where TLC analysis indicated thepresence of starting material. After rechilling to about -78° C., anadditional 1.03 ml of a 1.0M diisobutylaluminum hydride solution inhexane was added and the mixture was allowed to warm to about -30° C.The mixture was quenched with aqueous 1N HCl solution and after warmingto RT was extracted with EtOAc (2×25 ml). The combined organic layerswere dried (MgSO₄) and evaporated to 199 mg of a yellow oil.Purification of the oil by flash chromatography (15 g of silica gel)using a EtOAc-hexane eluant (3:2) afforded 163 mg of an oil whichspontaneously crystallized upon standing. Trituration with hexane-ether(3:1) afforded 69 mg of the title compound, mp 67°-69° C. ¹ H NMR(CDCl₃): δ1.39 (3H, s), 1.41-1.94 (6H, m), 2.61 (2H, t, J=8), 2.96 (1H,d, J=16), 3.44 (1H, d, J=16), 3.49-3.72(2H, m), 3.85 (3H, s), 4.00 (2H,t, J=7), 6.82 (1H, d, J=9), 6.99 (1H, dd, J=2, 9), 7.14-7.32 (6H, m).FABMS (m/e): 384 (M⁺ +1).

EXAMPLE 18 (+)-5-Ethyl -5-hydroxymethyl-3-4-methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazoline

The title compound was prepared as an oil substantially according to theprocedure of Example 13 substituting the compound of Preparation 25 forthe compound of Preparation 20. ¹ H NMR (CDCl₃): δ 0.98 (3H, t, J=7),1.52-1.93 (8H, m), 2.35-2.70 (1H, bd s), 2.65 (2H, t, J=7), 3.06 (1H, d,J=17), 3.36 (1H, d, J=17), 3.60 (1H, d, J=12), 3.75 (1H, d, J=12), 3.89(3H, s), 4.04 (2H, t, J=7), 6.85 (1H, d, J=8), 7.04 (1H, dd, J=2, 8),7.18-7.35 (6H, m). MS (m/e): 397, 362, 310, 91 (base). α!_(D) +20.1°(CHCl₃).

EXAMPLE 19 (-)-5-Ethyl-5-hydroxymethyl-3-4-methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazoline

The title compound was prepared as an oil substantially according to theprocedure of Example 13 substituting the compound of Preparation 26 forthe compound of Preparation 20. α!_(D) -16.3° (CHCl₃).

EXAMPLES 20-21

The following compounds were prepared as oils substantially according tothe procedure of Example 15 substituting the indicated aldehyde for thecompound of Example 9.

    ______________________________________                                         ##STR13##                                                                    Ex.  Aldehyde  α!.sub.D (CHCl.sub.3)                                                              .sup.1 H NMR(CDCl.sub.3):                           ______________________________________                                        20   Cmpd of  +8.9°                                                                              δ 0.93(3H, t, J=7), 1.36-1.90                      Ex. 11               (10H, m), 2.62(2H, t, J=8),                                                   3.03(1H, d, J=17), 3.34(1H,                                                   d, J=17), 3.52-3.74(2H, m),                                                   3.86(3H, s), 4.01(2H, t, J=7),                                                6.82(1H, d, J=8), 7.01(1H,                                                    dd, J=2, 8), 7.15-7.32(6H, m)                       21   Cmpd of  -9.8°                                                                              MS(m/e): 412(M.sup.+  + 1), 382,                         Ex 10                312                                                 ______________________________________                                    

EXAMPLES 22-28

The following compounds were prepared substantially according to theprocedure of Preparation 15 substituting the indicated olefin for ethylacrylate.

    __________________________________________________________________________     ##STR14##                                                                    Ex                                                                              R.sup.5                                                                              R.sup.4                                                                            R.sup.3                                                                             Olefin    M.P. °C.                                                                    Data                                       __________________________________________________________________________    22                                                                              H      H    H     CH.sub.2CH.sub.2                                                                        103-105                                                                            Anal. Calc'd. for                                                             C.sub.21 H.sub.25 NO.sub.3.1/4H.sub.2                                         O:                                                                            C, 73.33; H, 7.32; N,                                                         4.07. Found: C,                                                               73.56; H, 7.20; N, 4.13                    23                                                                              Me     Me   H     Me.sub.2 CCH.sub.2                                                                      83-85                                                                              Anal. Calc'd. for                                                             C.sub.23 H.sub.29 NO.sub.3.1/4H.sub.2                                         O:                                                                            C, 74.26; H, 7.85; N,                                                         3.36. Found: C,                                                               74.56; H, 7.90; N, 3.84                    24                                                                              COCH.sub.3                                                                           H    H     CH.sub.2CHCOCH.sub.3                                                                    oil  .sup.1 H NMR(CDCl.sub.3): δ                                             1.46-1.90(6H, m),                                                             2.35(3H, s), 2.62(2H,                                                         t, J=8), 3.39-3.62(2H,                                                        m), 3.86(3H, s), 4.01                                                         (2H, t, J=7), 4.97(1H,                                                        dd, J=6, 11), 6.83                                                            (1H, d, J=8), 7.03                                                            (1H, dd, J=2, 8), 7.15-                                                       7.33(6H, m)                                25                                                                              CONH.sub.2                                                                           H    H     CH.sub.2CHCONH.sub.2                                                                    152-154                                                                            Anal. Calc'd for                                                              C.sub.22 H.sub.26 N.sub.2 O.sub.4 : C,                                        69.08;                                                                        H, 6.85; N, 7.32.                                                             Found: C, 68.80; H,                                                           6.64; N, 7.26                              26                                                                              (CH.sub.2).sub.2 OH                                                                  H    H     CH.sub.2CH(CH.sub.2).sub.2 OH                                                           84-86                                                                              .sup.1 H NMR(CDCl.sub.3): δ                                             1.40-1.81(8H, m),                                                             2.59(2H, t, J=7), 3.05                                                        (1H, dd, J=8, 17),                                                            3.43(1H, dd, J=10,                                                            17), 3.52(2H, q, J=5),                                                        3.77(3H, s), 3.96(2H,                                                         t, J=6), 4.56(1H, t,                                                          J=5), 4.70-4.75(1H,                                                           m), 6.98(1H, d, J=8),                                                         7.12-7.29(7H, m), MS                                                          (m/e): 384(M.sup.+  + 1)                   27                                                                              H      CH.sub.2 OCH.sub.2 OCH.sub.2.sup.a                                                        ##STR15##                                                                              122-125                                                                            .sup.1 H NMR(CDCl.sub.3): δ                                             1.48-1.89(6H, m), 2.62(2H, t, J=8),                                           3.86 (3H, s), 3.91-4.40(8H, m),                                               4.69(1H, d, J=6), 4.87(1H, d, J=6),                                           6.86(1H, d, J=8), 7.03(1H, dd, J=2,                                           8), 7.17-7.32(6H, m), MS (m/e):                                               412(M.sup.+  + 1)                          28                                                                              CH.sub.2 NHCOCF.sub.3                                                                H    H     Preparation 14                                                                          91-94                                                                              .sup.1 H NMR(CDCl.sub.3): δ                                             1.39-1.94(6H, m),                                                             2.56(2H, t, J=7), 2.95                                                        (1H, dd, J=8, 16) 3.17                                                        (1H, dd, J=12, 16),                                                           3.17-3.48(1H, m),                                                             3.60-3.68(1H, m),                                                             3.91(3H, s), 3.95(2H,                                                         t, J=7), 4.72-4.82(1H,                                                        m), 6.64(1H, bd s),                                                           6.75(1H, d, J=8),                                                             6.92(1H, dd, J=2, 8)                                                          7.07-7.22(6H, m).                                                             FABMS(m/e): 465                                                               (M.sup.+  + 1)                             __________________________________________________________________________     .sup.a cis stereochemistry in the ring juncture                          

EXAMPLE 29 5-Aminomethyl-3-4-methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazoline Hydrochloride

A mixture of 250 mg (0.538 mmol) of the compound of Example 28, 5 ml ofMeOH, and 1 ml of water was treated with 91 mg (1.62 mmol) of KOH andwas allowed to stir for about 16 h at RT. The mixture was partiallyevaporated to remove MeOH and the residue was diluted with EtOAc (50 ml)and sat'd. aqueous NaHCO₃ solution (50 ml). The organic layer wasseparated and washed with an additional 50 ml of sat'd. aqueous NaHCO₃solution, dried (MgSO₄), and evaporated to an oil. NMR analysisindicated the presence of a small amount of starting material, so theoil was treated again as described above using 30 mg of KOH. Afterwork-up 126 mg of an oil was obtained, which was treated with HCl gas in3 ml of CHCl₃. The solvent was evaporated and the semi-solid residue wastriturated in ether to yield 70 mg of the title compound, mp 106°-109°C. Anal. Calc'd for C₂₂ H₂₈ N₂ O₃ HCl: C, 63.78; H, 7.00; N, 6.76.Found: C, 63.93; H, 7.29; N, 6.65.

EXAMPLE 30 5-Amino-3-4-methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazoline-5-carboxylic AcidHydrobromide

A mixture of 50 mg (0.094 mmol) of the compound of Preparation 30 and 2ml of bromotrimethylsilane was stirred for about 16 hr at RT. Aprecipitate was observed and a small amount of acetonitrile was addedand the mixture was heated to reflux. The mixture was evaporated and theresidue was triturated with ether to afford 57 mg of the title compound,mp 123°-127° C. ¹ H NMR (CD₃ OD): δ 1.47-1.88 (6H, m), 2.64 (2 H, t,J=7), 3.82 (1H, d, J=17), 3.88 (3H, s), 4.02 (2H, t, J=8), 4.29 (1 H, d,J=17), 7.03 (1H, d, J=8), 7.12-7.33 (7H, m). FABMS (m/e): 477, 399.

EXAMPLES 31-32 Racemic Diastereomers of 5-(1-Hydroxyethyl)-3-4-methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazoline

To a solution of 360 mg (0.944 mmol of the compound of Example 24 in 4ml of MeOH chilled to about 0° C. was added 36.0 mg (0.944 mmol ofNaBH₄. After the bubbling ceased, the ice bath was removed and stirringwas continued for about 1 h. Excess aqueous 1N HCl solution was addedand the mixture was partially evaporated to remove MeOH. The residue wasdiluted with 50 ml of water and extracted with EtOAc (2×50 ml). Thecombined EtOAc extracts were dried (MgSO₄) and evaporated to 360 mg ofan oil, which was separated by flash chromatography (50 g of silica gel)using ether-hexane (7:3) and ether as eluants. The fractions containingthe less polar diastereomer (R_(f) 0.28, ether) were combined andevaporated to 31 mg of an oil which was crystallized from hexane, mp102°-103° C. Anal. Calc'd for C₂₃ H₂₉ NO₄ : C, 72.04; H, 7.62; N, 3.65.Found: C, 72.22; H, 7.57; N, 3.41.

The fractions containing the more polar diastereomer (R_(f) 0.23, ether)were combined and evaporated to 117 mg of an oil which was crystallizedfrom hexane, mp 72°-74° C. Anal. Calc'd for C₂₃ H₂₉ NO₄ : C, 72.04; H,7.62; N, 3.65. Found: C, 72.26; H, 7.57; N, 3.50.

EXAMPLES 33-36

The following compounds were prepared by saponification of the indicatedester, substantially according to the procedure of Example 1.

    __________________________________________________________________________     ##STR16##                                                                    Ex.                                                                              R.sup.2 R.sup.4                                                                          Ester                                                                              M.P. °C.                                                                     Data                                                 __________________________________________________________________________    33 cyclopentyl                                                                           H  Cmpd. of                                                                           135-137                                                                             Anal. Calc'd for C.sub.16 H.sub.19 NO.sub.5 :                      Prep. 31   C, 62.94; H, 6.27; N, 4.59.                                                   Found: C, 62.82; H, 6.01; N,                                                  4.59.                                                34 cyclopentyl                                                                           Me Cmpd. of                                                                           149-151                                                                             Anal. Calc'd for                                                   Prep. 32   C.sub.17 H.sub.21,NO.sub.5.1/4H.sub.2 O: C,                                   62.99; H, 6.64; N, 4.32.                                                      Found: C, 63.22; H, 6.38; N,                                                  4.32.                                                35 (CH.sub.2).sub.4 Ph                                                                   H  Cmpd. of                                                                           108-110                                                                             .sup.1 H NMR(DMSO-d.sub.6): δ 1.60-                          Prep. 35   1.75(4H, m), 2.64(2H, t,                                                      J=6), 3.50-3.72(2H, m), 3.78                                                  (3H, s), 3.99(2H, t, J=6),                                                    5.11(1H, dd, J=3, 11), 6.99                                                   (1H, d, J=8), 7.16-7.30(7H,                                                   m).                                                  36                                                                                ##STR17##                                                                            H  Cmpd. of Prep. 33                                                                  oil   .sup.1 H NMR(CDCl.sub.3): δ 1.10-1.82 (8H,                              m), 2.28(1H, s), 2.49 (1H, d, J=2),                                           3.65-3.70(2H, m), 3.85(3H, s), 4.20(1H, d, J=4),                              5.18(1H, dd, J=5, 12), 6.82(1H, d, J=8),                                      7.01(1H, d, J=8), 7.27(1H, s).                       __________________________________________________________________________

EXAMPLE 37

3-(3-Cyclopentyloxy-4-methoxy)phenyl-2-isoxazoline-5-carboxaldehyde

To a solution of 250 mg (0.750 mmol) of the compound of Preparation 31in 5 ml of THF chilled to about -78° C. was added dropwise 1.88 ml (1.88mmol) of a 1M diisobutylaluminum hydride solution in hexane. The mixturewas stirred for about 30 min at about -78° C. and was quenched by theaddition of 3 ml of MeOH. Following the addition of 10 ml of 1N aqueousHCl solution, the mixture was allowed to warm to RT and was partiallyevaporated to remove THF and MeOH. The residue was extracted with EtOAc(2×50 ml) and the combined extracts were washed with sat'd. aqueousNaHCO₃ (2×30 ml), dried (Na₂ SO₄), and evaporated to 205 mg of an oil.Purification of the oil by flash chromatography (50 g of silica gel)using an EtOAc-hexane (1:1 to 3:1) eluant afforded 173 mg of the titlecompound as an oil. The NMR spectrum indicated partial hydration of thealdehyde. ¹ H NMR (CDCl₃): δ 1.50-2.05 (8H, m), 3.20-3.62 (2.5H, m),3.83 and 3.84 (3H, two s), 4.66-4.85 (1.5H, m), 4.98-5.07 (1H, m), 6.84(1H, d, J=8), 7.04 (1H, dd, J=2, 8), 7.35 (1H, d, J=2), 9.80 (0.5H, s).

EXAMPLE 38 3- -3-(S)-(exo)-Bicyclo2.2.1!hept-2-yloxy-4-methoxy!phenyl-5-methyl-2-isoxazoline-5-carboxaldehyde

The title compound was prepared as an oil by diisobutylaluminum hydridereduction of the compound of Preparation 34, substantially according tothe procedure of Example 8. ¹ H NMR (CDCl₃): δ 1.10-1.82 (8H, m), 1.56(3H, s), 2.25-2.50 (1 H, m), 2.49 (1H, d, J=1), 3.06 (1H, d, J=17), 3.65(1H, d, J=17), 3.84 (3H, s), 4.11 (1H, d, J=6), 6.81 (1H, d, J=6), 6.98(1H, dd, J=2, 8), 7.27 (1H, d, J=2), 9.67 (1H, s). MS (m/e): 330 (M⁺+1). α!_(D) -24.3° (CHCl₃).

EXAMPLES 39 and 40

The following compounds were prepared as oils by NaBH₄ reduction of theindicated aldehydes, substantially according to the procedure of Example15.

    __________________________________________________________________________     ##STR18##                                                                    Ex                                                                              R.sup.2 R.sup.4                                                                         Aldehyde                                                                             α!.sub.D (CHCl.sub.3)                                                         Data                                                 __________________________________________________________________________    39                                                                              cyclopentyl                                                                           H Cmpd. of     .sup.1 H NMR(CDCl.sub.3): δ 1.50-2.05                      Example 37   (8H, m), 3.15-3.36(2H, m),                                                    3.60-3.85(2H, m), 3.94(3H,                                                    s), 3.73-3.85(2H, m), 6.79                                                    (1H, d, J=8), 6.98(1H, dd,                                                    J=2, 8), 7.30(1H, d, J=2).                                                    FABMS(m/e): 292(M.sup.+  + 1)                        40                                                                               ##STR19##                                                                            Me                                                                              Cmpd. of Example 38                                                                 -4.8°                                                                         .sup.1 H NMR(CDCl.sub.3): δ 1.10-1.82 (m,                               8H), 1.39(3H, s), 1.97(1H, dd, J=5, 6),                                       2.24-2.28(1H, m), 2.49(1H, d, J=4), 2.97(1H, d,                               J=17), 3.43(1H, d, J=17), 3.52-3.73(2H, m),                                   3.84(3H, s), 4.21(1H, d, J=7), 6.81 (1H, d,                                   J=8), 7.10(1H, dd, J=2, 8) 7.28(1H, d, J=2).                                  FABMS(m/e): 332(M.sup.+  + 1)                        __________________________________________________________________________

EXAMPLE 41 3-4-Methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazolin-5-ylphosphonic Acid

A solution of 50 mg of the compound of Preparation 38 in 1 ml oftrimethylsilyl-bromide was stirred for about 2 h at RT. The mixture wasevaporated and the residue was diluted with water (4 ml) and CH₂ Cl₂ (3ml) and was stirred for about 2 h. The mixture was filtered and theaqueous layer was basified with aqueous 1N NaOH solution. The organiclayer was separated and the aqueous layer was washed with additional CH₂Cl₂ (2×15 ml). Acidification of the aqueous layer with aqueous 1N HClsolution, extraction with EtOAc (2×15 ml), drying (MgSO₄), andevaporation afforded 42 mg of the title compound as an oil. ¹ H NMR(DMSO-d₆): d 1.37-1.78 (6H, m), 2.58 (2H, t, J=7), 3.57-3.77 (2H, m),3.89 (3H, s), 3.96 (2H, t J=7), 4.61 (1H, t, J=10), 7.97 (1H, d, J=8),7.08-7.26 (7H, m), FABMS (m/e): 420 (M⁺ +1).

EXAMPLES 42-45

The following compounds were prepared in an analogous manner to theprocedure of Example 41 using as starting material the compounds fromthe indicated Preparations.

    __________________________________________________________________________     ##STR20##                                                                                   Cmpd                                                           Ex R.sup.2                                                                             R.sup.4                                                                          s  of Prep                                                                           M.P. °C.                                                                    Data                                                  __________________________________________________________________________    42 (CH.sub.2).sub.5 Ph                                                                 Me 0  39  175-177.sup.a                                                                      Calc'd. for C.sub.22 H.sub.28 NO.sub.6 P.H.sub.2                              O: C,                                                                         58.53; H, 6.65; N, 3.10. Found:                                               C, 58.27; H, 6.61; N, 3.16                            43 (CH.sub.2).sub.4 Ph                                                                 H  1  40  137-139                                                                            Calc'd. for                                                                   C.sub.22 H.sub.28 NO.sub.6 P.1/4H.sub.2 O: C,                                 60.28;                                                                        H, 6.51; N, 3.20. Found: C,                                                   60.17; H, 6.32; N, 3.19                               44 (CH.sub.2).sub.5 Ph                                                                 Me 1  41  112-115.sup.a                                                                      Calc'd. for C.sub.23 H.sub.30 NO.sub.6 P.H.sub.2                              O: C,                                                                         59.29; H, 6.87; N, 3.00. Found:                                               C, 58.99; H, 6.94; N, 2.97                            45 cyclopentyl                                                                         H  0  42  166-168                                                                            .sup.1 H NMR(DMSO-d.sub.6): d 1.50-1.90                                       (8H, m), 3.22-3.70(2H, m), 3.73                                               (3H, s), 4.56(1H, t, J=12), 4.72-                                             4.80(1H, m), 6.93(1H, d, J=8),                                                7.09(1H, d, J=8), 7.16(1H, s)                         __________________________________________________________________________     .sup.a recrystallized from EtOAc                                         

PREPARATION 1 4-Methoxy-3-(5-phenylpentyloxy)benzaldehyde Oxime

A mixture of 25.0 g (0.164 mol) of isovanillin, 26.9 g (0.164 mol) of5-phenyl-1-pentanol, 64.5 g (0.246 mol) of triphenylphosphine and 250 mlof THF was treated dropwise with 42.8 g (0.246 mol) of diethylazodicarboxylate. The mixture was heated to about 90° C. for about 6 hand then stirred overnight at RT. The solvent was evaporated and theresidue was diluted with 500 ml of EtOAc, washed with water (1×400 ml),1N NaOH solution (2×400 ml), brine (1×400 ml), dried (MgSO₄), andevaporated to 119 g of a brown oil. Purification by flash chromatography(750 g of silica gel) using an EtOAc-hexane (3:7) eluant afforded 29.8 g(61%) of the title compound as an oil. ¹ H NMR (CDCl₃): δ 1.42-1.92 (6H,m), 2.61 (2H, t, J=7), 3.91 (3H, s), 4.03 (2H, t, d=7), 6.91 (1H, d,J=8), 7.10-7.40 (m, 7H), 9.77 (s, 1H)

To a solution of 29.8 g (0.100 mol) of the aldehyde above in 300 ml of95% ethanol was added 13.7 g (0.197 mol) of hydroxylamine hydrochloridein 100 ml of water followed by 16.6 g (0.197 mol) of sodium bicarbonatein small portions (gas evolution|). The mixture was stirred for about 4h at RT and the ethanol was removed by evaporation. The residue wasdiluted with 250 ml of water and extracted with EtOAc (2×200 ml). Thecombined extracts were dried (MgSO₄) and evaporated to a yellow oilwhich was crystallized from hexane/ether to afford 15.0 g of the titlecompound, mp 65°-67° C. ¹ H NMR (CDCl₃): δ 1.46-1.93 (6H, m), 2.62 (2H,t, J=7), 3.88 (3H, s), 4.02 (2H, t, J=7), 6.99-7.62 (m, 6H), 7.49 (1H,s), 8.04 (1H, s).

An additional 2.00 g of product was obtained as a second crop from thefiltrate, mp 67°-69° C. Evaporation of the filtrate and purification ofthe residue by flash chromatography using an EtOAc-hexane (2:3) eluantalso provided an additional 4.18 g of product, mp 64°-66° C.

PREPARATIONS 2-4

Reaction of the appropriate alcohol with isovanillin and condensation ofthe resulting aldehyde with hydroxylamine hydrochloride, substantiallyaccording to the procedure of Preparation 1, afforded the followingcompounds as oils.

    ______________________________________                                         ##STR21##                                                                    Prep. #                                                                             R.sup.2     .sup.1 H NMR CDCl.sub.3, δ                            ______________________________________                                        2     (CH.sub.2).sub.4 Ph                                                                       1.70-1.90(m, 4H), 2.65(2H, t, J=7),                                           3.95(3H, s), 4.10(2H, t, J=7), 6.90(1H, d,                                    J=8), 6.94-7.26(6H, m), 6.97(1H, dd,                                          J=2, 8), 7.56(1H, s), 8.01(1H, s)                           3     cyclopentyl 1.50-2.02(8H, m), 3.94(3H, s),                                                4.62-4.80(1H, m), 6.91(1H, d, J=8),                                           6.97(1H, dd, J=8 and 1), 7.17(1H, d, J=1),                                    8.02(1H, s), 8.16(1H, s)                                           ##STR22##  1.10-1.80(8H, m), 2.26-2.32(1H, m), 2.47-2.52(1H, m),                         3.84(3H, s), 4.21(1H, d, J=7), 6.82(1H, d, J=8),                              6.98(1H, dd, J=8 and 2), 7.13(1H, d, J=2), 7.78(1H, s),                       .03(1H, s)                                                  ______________________________________                                    

PREPARATION 5 Ethyl 2-Methylenebutyrate

A mixture of 5.0 g (0.019 mol) of triethyl 2-phosphonobutyrate, 5.5 g(0.039 mol) of K₂ CO₃, 6.2 g (0.076 mol) of 37% aqueous formaldehydesolution, and 15 ml of water was heated to about 80° C. for about 45min. After cooling to RT, 75 ml of ether was added and the organic layerwas separated, washed with brine (1×20 ml), dried (MgSO₄), and filtered.The ether was carefully removed by distillation, leaving behind 2.1 g(87%) of the title compound as a clear oil which was used directlywithout further purification. ¹ H NMR (CDCl₃): δ 1.01 (3H, t, J=7), 1.24(3H, t, J=7), 2.26 (2H, q, J=7) 4.14 (2H, q, J=7), 5.45 (1H, s), 6.06(1H, s).

PREPARATION 6 Ethyl 2-Methylenepentanoate

Reaction of triethyl 2-phosphonopentanoate, substantially according tothe procedure of Preparation 5, gave the title compound as an oil. ¹ HNMR (CDCl₃): δ 1.05 (3H, t, J=7), 1.28 (3H, t, J=7), 1.41-1.53 (2H, m),2.87 (2H, q, J=7), 4.18 (2H, q, J=7), 5.49 (1H, s), 6.11 (1H, s).

PREPARATION 7 2-Methylenebutyric Acid

To a solution of 5.08 g (39.6 mmol) of the compound of Preparation 5 in95 ml of EtOH and 40 ml of water was added 1.58 g (39.6 mmol) of solidNaOH, and the mixture was stirred for about 2 h at RT. An additional0.15 g of NaOH was added and stirring was continued for about 2 h. Themixture was partially evaporated to remove the EtOH and the residue wasdiluted with 20 ml of H₂ O and acidified to pH 2 with aqueous 6N HClsolution. Extraction with EtOAc, drying (MgSO₄), and evaporationafforded 2.49 g (63%) of the title compound as an oil. ¹ H NMR (CDCl₃):δ 1.11 (3H, t, J=7), 2.34 (2H, q, J=7), 5.66 (1H, s), 6.30 (1H, s),11.78 (1H, bd s).

PREPARATION 8 2-Methylenepentanoic Acid

Reaction of the compound of Preparation 6, substantially according tothe procedure of Preparation 7, gave the title compound as an oil. ¹ HNMR (CDCl₃): δ 0.91 (3H, t, J=7), 2.40-2.54 (2H, m), 2.26 (2H, t, J=7),5.62 (1H, s), 6.27 (1H, s).

PREPARATION 9 (S)-(-)-(N-α-Methylbenzyl)acrylamide

To a solution of 5.0 g (0.055 mol) of acryloyl chloride in 30 ml of CH₂Cl₂ chilled to about 0° C. was added dropwise 7.1 ml (6.7 g, 0.055 mol)of (S)-(-)-α-methylbenzylamine. After the exotherm had subsided, 8.5 ml(6.2 g, 0.061 mol) of triethylamine was added dropwise and the mixturewas allowed to warm to RT. Following about 2 h of additional stirring,the solvent was removed by evaporation and the residue was taken up in200 ml of EtOAc and washed with aqueous 1N HCl solution, aqueous sat'd.NaHCO₃ solution, dried (MgSO₄), and evaporated to a solid. Triturationin hexane-ether afforded 7.8 g of the title compound as a solid, mp97°-99° C. ¹ H NMR (CDCl₃): δ 1.50 (3H, d, J=7), 5.11-5.21 (1H, m), 5.63(1H, dd, J=2, 10), 5.77 (1H, bd s), 6.06 (1H, dd, J=10, 13), 6.26 (1H,dd, J=1, 17), 7.19-7.32 (5H, m).

PREPARATION 10 (S)-(-)-(N-α-Methylbenzyl)-2-methylpropionamide

To a solution of 5.00 g (0.0581 mol) of methacrylic acid in 100 ml ofTHF was added 7.03 g (0.0581 mol) of (S)-(-)-α-methylbenzylamine, 7.84 g(0.0581 mol) of hydroxybenztriazole, and 11.1 g (0.0581 mol) of1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride. Afterstirring for about 4 h at RT, the solvent was removed by evaporation andthe residue was taken up in 200 ml of BOAc and washed with water (2×100ml), aqueous 1N HCl solution (2×100 ml), sat'd. aqueous NaHCO₃ solution,dried (MgSO₄), and evaporated to solid. Trituration in hexane-ether(2:1) afforded 8.68 g of the title compound as a white solid, mp 95°-98°C. ¹ H NMR (CDCl₃): δ 1.51 (3H, d, J=7), 1.93 (3H, s), 5.09-5.19 (1H,m), 5.29 (1H, s), 5.65 (1H, s), 5.95 (1H, bd s), 7.20-7.34 (5H, m).

PREPARATIONS 11-13

Reaction of the appropriate acid with (R)-(+)-α-methylbenzylamine,substantially according to the procedure of Preparation 10, afforded thefollowing compounds.

    __________________________________________________________________________     ##STR23##                                                                    Prep. #                                                                            Q  Acid  M.P. °C.                                                                    .sup.1 H NMR CDCl.sub.3, δ                           __________________________________________________________________________    11   Me Methacryclic                                                                        93-95                                                                              1.53(3H, d, J=7), 1.97(3H, s), 5.10-5.23                           acid       (1H, m), 5.23(1H, s), 5.64(1H, s), 6.01(1H,                                   bd s), 7.25-7.37(5H, m)                                    12   Et Cmpd of                                                                             oil  1.07(3H, t, J=7), 1.53(3H, d, J=7), 2.34                           Prep 7     (2H, q, J=7), 5.13-5.25(1H, m), 5.26(1H,                                      s), 5.59(1H, s), 6.06(1H, bd s), 7.20-7.35                                    (5H, m)                                                    13   Pr Cmpd of                                                                             69-71                                                                              0.91(3H, t, J=7), 1.29-1.54(2H, m), 1.53                           Prep 8     (3H, d, J=8), 2.28(2H, t, J=8), 5.12-5.22                                     1H, m), 5.24(1H, s), 5.57(1H, s), 5.96(1H,                                    bd s), 7.25-7.36(5H, m)                                    __________________________________________________________________________

PREPARATION 14 (N-Trifluoroacetyl)allylamine

A solution of 9.97 g (0.175 mol) of allylamine in 100 ml of pyridinechilled to about 0° C. was treated dropwise with 37.2 g (0.175 mol) oftrifluoroacetic anhydride. After about 2 h of stirring the solvent wasremoved by evaporation. The residue was taken up in 200 ml of CH₂ Cl₂and washed with aqueous 1N HCl solution (2×100 ml), sat'd. aqueousNaHCO₃ solution, dried (Na₂ SO₄), and evaporated to give 18.9 g (79%) ofthe title compound as an oil. ¹ H NMR (CDCl₃): d 3.97 (2H, t, J=5), 5.20(1H, s), 5.27 (1H, d, J=10), 5.74-5.88 (1H, m), 6.57 (1H, bd s).

PREPARATION 15 3-4-Methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazoline-5-carboxylic AcidEthyl Ester

To a mixture of 1.28 g (9.57 mmol) of N-chlorosuccinimide, 200 μl ofpyridine, and 200 ml of CH₂ Cl₂ was added 2.00 g (6.38 mmol) of thecompound of Preparation 1 in a solution of 15 ml of CH₂ Cl₂. An exothermwas observed after about 10 min and following about 2 h of stirring atRT, 644 mg (698 μl, 6.38 mmol) of ethyl acrylate was added followed by966 mg (1.33 ml, 9.57 mmol) of triethylamine. After the exothermsubsided, the mixture was stirred for about 2 h at RT. The mixture wasdiluted with 250 ml of CH₂ Cl₂ and washed with aqueous 1N HCl solution,sat'd. aqueous NaHCO₃ solution, dried (Na₂ SO₄), and evaporated to anoil. Purification by flash chromatography (100 g of a silica gel) usingan EtOAc-hexane (2:3) eluant afforded 1.82 g (69%) of the title compoundas an oil. ¹ H NMR (CDCl₃): δ 1.29 (3H, t, J=7), 1.40-1.91 (6H, m), 2.60(2H, t, J=7), 3.55-3.58 (2H, m), 3.95 (3H, s), 3.99 (2H, t, J=7) 4.22(2H, q, J=7), 5.05-5.12 (1H, m), 6.79 (1H, d, J=8), 6.95-7.31 (7H, m).

PREPARATIONS 16-30

The following compounds were prepared substantially according to theprocedure in Preparation 15 substituting the indicated olefin for ethylacrylate.

    __________________________________________________________________________     ##STR24##                                                                    Prep #                                                                            R.sup.5     R.sup.4                                                                           R.sup.3                                                                          Olefin M.P. °C.                                                                    Data                                       __________________________________________________________________________    16  CO.sub.2 Et Me  H  Ethyl  oil  .sup.1 H NMR (CDCl.sub.3): δ                                            1.25(3H, t, J=7), 1.37-1.90(6H, m),                                           1.64                                                              α-methacrylate                                                                      (3H, s), 2.54(2H, t, J=7), 3.11(1H, d,                                        J=15), 3.77(1H, d, J=15),                                                     3.83(3H, s), 3.95(2H, q, J=7),                                                4.17(2H, q, J=7), 6.75(1H, d, J=8),                                           6.90-8.28(7H, m)                           17  CO.sub.2 Et H   Me.sup.a                                                                         Ethyl  oil  MS(m/e): 425(M.sup.+), 279, 91(base)                              crotonate                                              18  CO.sub.2 Et Et  H  Cmpd of                                                                              oil  MS(m/e): 439(M.sup.+), 310, 105                                   Prep 5                                                 19  CO.sub.2 Et Pr  H  Cmpd of                                                                              oil  FABMS(m/e): 454(M.sup.+), 380, 310                                Prep 6                                                 20  (S)CONHCH(Me)Ph.sup.b                                                                     H   H  Cmpd of                                                                              85-90                                                                              Anal. Calc'd for C.sub.30 H.sub.34                                            N.sub.2 O.sub.4 : C, 74.05; H, 7.04;                                          N, 5.76.                                                          Prep 9      Found: C, 74.16; H, 6.93; N, 5.88.         21  (S)CONHCH(Me)Ph.sup.c                                                                     H   H  Cmpd of                                                                              91-101                                                                             Anal. Calc'd for C.sub.30 H.sub.34                                            N.sub.2 O.sub.4 : C, 74.05; H, 7.04;                                          N, 5.76.                                                          Prep 9      Found: C, 74.32; H, 6.94; N, 5.71.         22  (S)CONHCH(Me)Ph.sup.d                                                                     Me  H  Cmpd of                                                                              113-116                                                                            Anal. Calc'd for C.sub.31 H.sub.36                                            N.sub.2 O.sub.4 : C, 74.37; H, 7.25;                                          N, 5.60.                                                          Prep 10     Found: C, 74.17; H, 6.87; N, 5.53          23  (R)CONHCH(Me)Ph.sup.e                                                                     Me  H  Cmpd of                                                                              97-99                                                                              Anal. Calc'd for C.sub.31 H.sub.36                                            N.sub.2 O.sub.4.1/4 H.sub.2 O: C,                                             73.64; H, 7.23; N, 5.55.                                          Prep 11     Found: C, 73.83; H, 7.35; N, 5.60          24  (R)CONHCH(Me)Ph.sup.f                                                                     Me  H  Cmpd of                                                                              111-113                                                                            Anal. Calc'd for C.sub.31 H.sub.36                                            N.sub.2 O.sub.4 : C, 74.37; H, 7.25;                                          N, 5.60.                                                          Prep 11     Found: C, 74.51; H, 7.22; N, 5.43          25  (R)CONHCH(Me)Ph.sup.g                                                                     Et  H  Cmpd of                                                                              126-130                                                                            .sup.1 H NMR (CDCl.sub.3): δ                                            1.06(3H, t, J=7), 1.53(3H, d, J=7),                                           1.53-2.21                                                         Prep 12     (8H, m), 2.65(2H, t, J=7); 3.23(1H, d,                                        J=17), 3.67(1H, d, J=17),                                                     3.89(3H, s), 4.02(2H, t, J=7),                                                5.02-5.15(1H, m), 6.85(1H, d, J=8),                                           7.02(1H, dd, J=2, 8), 7.16-7.32(12H,                                          m)                                         26  (R)CONHCH(Me)Ph.sup.g                                                                     Et  H  Cmpd of                                                                              121-123                                                                            .sup.1 H NMR (CDCl.sub.3): δ                                            0.92(3H, t, J=7), 1.47(3H, d, J=7),                                           1.47-2.18                                                         Prep 12     (8H, m), 2.66(2H, t, J=7), 3.26(1H, d,                                        J=17), 3.76(1H, d, J=17),                                                     3.90(3H, s), 4.04(2H, t, J=7),                                                5.02-5.13(1H, m), 6.87(1H, d, J=8),                                           7.07(1H, dd, J=2, 8), 7.18-7.36(12H,                                          m)                                         27  (R)CONHCH(Me)Ph.sup.h                                                                     Pr  H  Cmpd of                                                                              123-125                                                                            Anal. Calc'd for C.sub.33 H.sub.40                                            N.sub.2 O.sub.4.1/4 H.sub.2 O: C,                                             74.27, H, 7.60, N, 5.35.                                          Prep 13     Found: C, 74.44; H, 7.50; N, 5.21          28  (R)CONHCH(Me)Ph.sup.i                                                                     Pr  H  Cmpd of                                                                              118-120                                                                            Anal. Calc'd for C.sub.33 H.sub.40                                            N.sub.2 O.sub.4.1/4 H.sub.2 O: C,                                             74.27; H, 7.60; N, 5.25.                                          Prep 13     Found: C, 74.08; H, 7.85; N, 5.19          29  OAc         H   H  Vinyl  oil  .sup.1 H NMR (CDCl.sub.3): δ                                            1.46-1.95(6H, m), 2.17(3H, s),                                                2.62(2H, t,                                                       acetate     J=8), 3.30(1H, d, J=18), 3.54-3.60(1H,                                        m), 3.87(3H, s), 4.02(2H,                                                     t, J=7), 5.27(1H, d, J=1),                                                    6.82-7.30(8H, m)                           30  CO.sub.2 Me NHCO.sub.2                                                                        H  H.sub.2 CH                                                                           oil  .sup.1 H NMR (CDCl.sub.3): δ                                            1.35 -1.84(6H, m), 2.55(2H, t, J=7),                                          3.89                                                       Bn     (NHCO.sub.2 Bn)                                                                           (3H, s), 3.93(2H, bd s), 3.94(2H, t,                                          J=7), 4.01(3H, s), 5.01(2H, s),                                   CO.sub.2 Me 6.30(1H, bd s), 6.73(1H, d, J=8),                                             6.90-7.33(12H, m)                          __________________________________________________________________________     .sup.a trans stereochemistry                                                  .sup.b less polar diastereomer  R.sub.f 0.23 (1:3 EtOAchexane)                .sup.c more polar diastereomer  R.sub.f 0.16 (1:3 EtOAchexane)                .sup.d more polar diastereomer  R.sub.f 0.42 (1:1 EtOAchexane)                .sup.e less polar diastereomer  R.sub.f 0.48 (1:1 EtOAchexane)                .sup.f more polar diastereomer  R.sub.f 0.42 (1:1 EtOAchexane)                .sup.g diastereomers of examples 25 and 26 were separated by fractional       crystallization                                                               .sup.h less polar diastereomer  R.sub.f 0.30 (3:7 EtOAchexane)                .sup.i more polar diastereomer  R.sub.f 0.26 (3:7 EtOAchexane)           

PREPARATIONS 31-32

The following compounds were prepared substantially according to theprocedure in Preparation 15 substituting the compound of Preparation 3for the compound of Preparation 1 and substituting the indicated olefinfor ethyl acrylate.

    __________________________________________________________________________     ##STR25##                                                                    Prep #                                                                            R.sup.5                                                                           R.sup.4                                                                           R.sup.3                                                                          Olefin M.P. °C.                                                                    Data                                               __________________________________________________________________________    35  CO.sub.2 Et                                                                       H   H  Ethyl  oil  .sup.1 H NMR (CDCl.sub.3): δ 1.27(3H, t,                                J=7), 1.45-2.00(8H, m), 3.56(2H, d,                               acrylate    J=10), 3.82(3H, s), 4.22(2H, q, J=7),                                         4.72-4.80(1H, m), 5.09(1H, t,                                                 J=10), 6.78(1H, d, J=8), 6.98(1H, d, J=8),                                    7.32(1H, s)                                        32  CO.sub.2 Et                                                                       Me  H  Ethyl  77-79                                                                              .sup.1 H NMR (CDCl.sub.3): δ 1.25(3H, t,                                J=7), 1.50-2.00(8H, m), 1.63(3H,                                  methacrylate                                                                              s), 3.11(1H, d, J=17), 3.78(1H, d, J=17),                                     3.91(3H, s), 4.18(2H, q,                                                      J=7), 4.68-4.77(1H, m), 6.75(1H, d, J=8),                                     6.92(1H, dd, J=8, 2),                                                         7.27(1H, d, J=2)                                   __________________________________________________________________________

PREPARATIONS 33-34

The following compounds were prepared substantially according to theprocedure of Preparation 15 substituting the compound of Preparation 4for the compound of Preparation 1 and substituting the indicated olefinfor ethyl acrylate.

    __________________________________________________________________________     ##STR26##                                                                    Prep #                                                                            R.sup.5     R.sup.4                                                                          R.sup.3                                                                          Olefin M.P. °C.                                                                    Data                                        __________________________________________________________________________    33  CO.sub.2 Et H  H  Ethyl  oil  .sup.1 H NMR (CDCl.sub.3): δ                                            1.05-1.77(8H, m), 1.27(3H, t, J=7),                                           2.05(1H,                                                          acrylate    bd s), 2.43(1H, bd s), 3.55(2H, d,                                            J=10), 3.92(3H, s), 4.15-4.23(1H,                                             m), 4.21(2H, q, J=7), 5.05(1H, t,                                             J=10), 6.77(1H, d, J=8), 6.95(1H,                                             d, J=8), 7.25(1H, s)                        34  (R)CHNHCH(Me)Ph                                                                           Me H  Cmpd of                                                                              151-153                                                                            .sup.1 H NMR (CDCl.sub.3): δ                                            1.10-1.75(8H, m), 1.44(3H, d, J=7),                                           1.65(3H,                                                          Prep 11.sup.a                                                                             s), 2.30(1H, bd s), 2.50(1H, bd d,                                            J=4), 3.18(1H, d, J=17), 3.81(1H,                                             d, J=17), 3.85(3H, s), 4.21(1H, d,                                            J=7), 4.99-5.08(1H, m), 6.83(1H,                                              d, J=8), 7.02(1H, dd, J=8, 2), 7.12(1H,                                       d, J=9), 7.20-7.36(6H,                      __________________________________________________________________________                                      m)                                           .sup.a less polar diastereomer  R.sub.f 0.4 (3:7 EtOAchexane)            

PREPARATION 35 3-4-Methoxy-3-(5-phenylbutyloxy)!phenyl-2-isoxazoline-5-carboxylic AcidEthyl Ester

The compound of this Preparation was prepared as an oil, substantiallyaccording to the procedure of Preparation 15, substituting the compoundof Preparation 2 for the compound of Preparation 1. ¹ H NMR (CDCl₃): δ1.31 (3H, t, J=7), 1.74-1.94 (4H, m), 2.68 (2H, t, J=7), 3.57-3.61 (2H,m), 3.87 (3H, s), 4.03 (2H, t, J=6), 4.25 (2H, q, J=7), 5.12 (1H, t,J=8), 6.83 (1H, d, J=8), 7.03 (1H, d, J=8), 7.16-7.35 (6H, m).

PREPARATION 36 Dimethyl Propenyl-2-phosphonate

The title compound was prepared as described by the method of Benezra,et al. (Benezra, C.; Nseic, S.; Qurisson, G. Bull. Chem. Soc. Chim. Fr.,1967, 1140.)

Into a flask fitted with a reflux condenser was placed a mixture of 37ml (29 g, 0.50 mol) of acetone and 46 ml (55 g, 0.50 ml) ofdimethylphosphite followed by 3 ml of saturated methanolic sodiummethoxide solution. A vigorous exotherm ensued and the mixture wasallowed to stir at RT for about 16 h. A large deposit of crystals formedand were filtered and washed well with ether-hexane (1:1) to give 50 gof dimethyl 1-hydroxy-1-methylethylphosphonate, mp 75°-77° C.

A solution of 6.00 g (35.7 mmol) of dimethyl1-hydroxy-1-methylethyl-phosphonate in 25 ml of pyridine was treateddropwise with 8.56 g (5.25 ml, 72.0 mmol) of thionyl chloride. Themixture was allowed to stir for about 16 h at RT and the solvent wasremoved by evaporation. The residue was diluted with 200 ml of water andextracted with EtOAc (3×200 ml). The combined extracts were dried (Na₂SO₄) and evaporated to 4.12 g of a yellow oil which was purified byflash chromatography (100 g of silica gel) using EtOAc as eluant toyield 3.46 g of the title compound as an oil.

PREPARATION 37 Diethyl 2-Methyl-1-propenyl-3-phosphonate

A mixture of 5.0 g (0.037 mol) of methallyl bromide and 15 g (0.087 mol)of triethyl phosphite was heated to about 160° C. for about 5 h.Purification of the crude reaction mixture by flash chromatography (300g of silica gel) using an EtOAc-hexane (3:2) eluant afforded 3.6 g (50%)of the title compound as a light yellow oil. ¹ H NMR (CDCl₃): d 1.31(6H, t, J=7), 1.87 (3H, d, J=3), 2.56 (2H, d, J=20), 4.03-4.13 (4H, m),4.82-4.92 (2H, m).

PREPARATION 38 Diethyl 3-4-Methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazolin-5-ylphosphonate

To a mixture of 1.02 g (7.76 mmol) of N-chlorosuccinimide, 0.05 ml ofpyridine, and 30 ml of CH₃ Cl₂ was added 2.00 g (6.38 mmol) of thecompound Preparation 1 in 10 ml of CH₂ Cl₂. The mixture was stirred forabout 45 min at RT and 1.05 g (0.980 ml, 6.38 mmol) of diethylvinylphosphonate was added followed by 0.777 g (1.07 ml, 7.66 mmol) oftriethylamine. An exotherm ensued and the mixture became dark yellow.After stirring for about 2 h at RT, the mixture was diluted to 150 mlwith CH₂ Cl₂ and was washed with aqueous 1N HCl solution (2×100 ml),sat'd. aqueous NaHCO₃ solution (2×100 ml), dried (MgSO₄), and evaporatedto 3.75 g of a yellow oil. Purification by flash chromatography (150 gof silica gel) using successively EtOAc-hexane (1:3), EtOAc, andMeOH--CHCl₃ (1:9) as eluants afforded 1.09 g of the title compound as anoil. ¹ H NMR (CDCl₃): d 1.30 (3H, t, J=7), 1.34 (3H, t, J=7), 1.40-1.90(6H, m), 2.60 (2H, t, J=7), 3.52-3.65 (2H, m), 3.95 (3H, s), 3.99 (2H,t, J=7), 4.16-4.25 (4 H, m), 4.80 (1H, t, J=12), 6.80 (1H, d, J=8),6.98-7.29 (7H, m).

PREPARATION 39-42

Reaction of the indicated oxime and olefin, analogous to the procedureof Preparation 38, afforded compounds having the following generalstructure: ##STR27##

39. R² is (CH₂)₅ Ph; R⁴ is methyl; R⁵ is methyl; s is 0; the oxime isthe compound of Preparation 1; the olefin is the compound of Preparation36; M.P. 91°-93° C.; ¹ H NMR (CDCl₃): d 1.46-1.92 (6H, m), 1.64 (3H, d,J=15), 2.62 (2H, t, J=7), 3.18 (1H, dd, J=17 and 19), 3.75-3.88 (10H,m), 4.00 (2H, t, J=7), 6.83 (1H, d, J=8), 7.00 (1H, d, J=8, 2),7.14-7.33 (6H, m).

40. R² is (CH₂)₅ Ph; R⁴ is H; R⁵ is ethyl; s is 1; the oxime is thecompound of Preparation 1; the olefin is diethyl allylphosphonate; ¹ HNMR (CDCl₃): d 1.32 (3H, t, J=7), 1.34 (3H, t, J=7), 1.37-2.38 (8H, m),2.61 (2H, t, J=7), 3.22 -3.52 (2H, m), 3.86(3H, s), 4.00 (2H, t, J=7),4.06-4.18 (4H, m), 4.82-4.96 (1H, m), 6.82 (1H, d, J=8), 7.03 (1H, dd,J=2, 8), 7.13-7.33 (6H, m).

41. R² is (CH₂)₅ Ph; R⁴ is methyl; R⁵ ethyl; s is 1; the oxime is thecompound of Preparation 1; the olefin is the compound of Preparation 37;¹ H NMR (CDCl₃): d 1.30 (3H, t, J=7), 1.32 (3H, t, J=7), 1.28-1.90 (6H,m), 2.30 (2H, d, J=19), 2.61 (2H, t, J=7), 3.08 (1H, d, J=17), 3.63 (1H,d, J=17), 3.86 (3H, s), 4.00 (2H, t, J=7 ), 4.00-4.18 (4H, m), 6.82 (1H,d, J=8), 6.99 (1H, dd, J=2, 8), 7.11-7.32 (6H, m).

42. R² is cyclopentyl; R⁴ is H; R⁵ is ethyl, s is 0, the oxime is thecompound of Preparation 3; the olefin is diethyl vinylphosphonate; ¹ HNMR (CDCl₃): d 1.31 (3H, t, J=7), 1.35 (3H, t, J=7), 1.50-2.00 (8H, m),3.56-3.67 (2H, m), 3.85 (3 H, s), 4.17-4.25 (4H, m), 4.78-4.82 (2H, m),6.83 (1H, d, J=8), 7.02 (1H, dd, J=2, 8), 7.32 (1H, d, J=2).

What is claimed is:
 1. A compound of the formula ##STR28## the racemic,racemic-diastereomeric mixtures and optical isomers of said compound andthe pharmaceutically acceptable salts thereof whereinY¹ is --OR¹ and isattached to the 4-position of the phenyl ring and Y² is --OR² and isattached to the 3-position of the phenyl ring;R¹ is alkyl having 1 to 3carbons, fluoromethyl, difluoromethyl or trifluoromethyl; R² is (C₃-C₇)cycloalkyl, optionally substituted phenylalkyl having 1 to 6 carbonsin the alkyl portion or bicycloalkyl having 6 to 9 carbons;wherein thearomatic portion of the optionally substituted phenylalkyl is optionallyindependently substituted with (C₁ -C₄) alkyl, (C₁ -C₄) alkoxy, halogenor CF₃ ; R³ is hydrogen, (C₁ -C₃)alkyl, mono-hydroxyalkyl having 1 to 3carbons or alkoxyalkyl having 1 to 3 carbons in the alkyl portion and 1to 3 carbons in the alkoxy portion; R⁴ is hydrogen, (C₁ -C₅)alkyl,--COOH, alkoxyalkyl having 1 to 3 carbons in the alkyl portion and 1 to3 carbons in the alkoxy portion, N-alkylaminoalkyl having 1 to 3 carbonsin the alkylamino portion and 1 to 3 carbons in the alkyl portion orN,N-dialkylaminoalkyl having a total of 2 to 6 carbons in thedialkylamino portion and 1 to 3 carbons in the alkyl portion; or R³ andR⁴ are taken together with the carbon atoms to which they are attachedand form --CH₂ OCH₂ OCH₂ --; and R⁵ is hydrogen, --CHO, amino,aminoalkyl having 1 to 3 carbons, ##STR29## mono-hydroxyalkyl having 1to 3 carbons, --(CH₂)_(b) --COOR⁶, --COR⁷, --(CH₂)_(m) CO₂ H, (C₁ -C₄)alkyl, hydroxy, --(CH₂)_(q) CONX² X³, --(CH₂)_(r) SO₂ NX⁴ X⁵,--(CH₂)_(s) PO₃ H₂ or ##STR30## wherein b is 0 or an integer from 1 to6; m, n, q, r, s and t are independently 0, 1, 2, 3 or 4; R⁶ and R⁷ areeach independently (C₁ -C₄)alkyl; X¹ is hydrogen, (C₁ -C₄) alkyl, --O(C₁-C₄) alkyl or alkoxyphenyl having one to four carbon atoms in the alkoxyportion; X², X³, X⁴ and X⁵ are each independently hydrogen or (C₁ -C₃)alkyl; and X⁶ is (C₁ -C₃)alkyl or phenyl;provided that when R⁴ is --COOHthen R⁵ is not --COOH.
 2. A compound according to claim 1 wherein R¹ ismethyl; R² is (C₃ -C₇)cycloalkyl, bicycloalkyl having 6 to 9 carbons, orphenylalkyl having 1 to 6 carbons in the alkyl portion; R³ is hydrogenor (C₁ -C₃)alkyl; R⁴ is hydrogen or (C₁ -C₅)alkyl and R⁵ is --(CH₂)_(m)CO₂ H, --CHO, --COCH₃, amino, hydroxy, mono-hydroxyalkyl having 1 to 3carbons, aminoalkyl having 1 to 3 carbons, or ##STR31## wherein X¹ is(C₁ -C₄)alkyl or alkoxyphenyl having one to four carbon atoms in thealkoxy portion and n is 0 or an integer from 1 to
 3. 3. A compoundaccording to claim 2 wherein R² is cyclopentyl or phenylalkyl having 4or 5 carbons in the alkyl portion.
 4. A compound according to claim 3wherein R² is 5-phenylpentyl.
 5. A compound according to claim 4 whereinR⁵ is --(CH₂)_(m) CO₂ H, --CHO, --COCH₃, hydroxy or mono-hydroxyalkylhaving 1 to 3 carbons.
 6. A compound according to claim 5 wherein R⁵ is--(CH₂)_(m) CO₂ H.
 7. A compound according to claim 6 wherein R⁵ ishydrogen; R⁴ is hydrogen or (C₁ -C₅)alkyl and m=0.
 8. A compoundaccording to claim 7 wherein R⁴ is hydrogen, methyl, ethyl or propyl. 9.A compound according to claim 8 wherein the compound is (+) or(-)-5-ethyl-3-4-methoxy-3-(5-phenylpentyloxy)!-phenyl-2-isoxazoline-5-carboxylic acid.10. A compound according to claim 9 wherein the compound is(-)-5-ethyl-3-4-methoxy-3-(5-phenylpentyloxy)!phenyl-2-isoxazoline-5-carboxylic acid.11. A compound according to claim 1 wherein R is CH₃ ; R is5-phenyl-pentyl; R³ is hydrogen; R⁴ is hydrogen or CH₃ and R⁵ is--(CH₂)_(s) PO₃ H₂ wherein s is 0 or
 1. 12. A compound according toclaim 1 wherein R¹ is CH₃ ; R² is cyclopentyl; R³ is hydrogen; R⁴ ishydrogen and R⁵ is --(CH₂)_(s) PO₃ H₂ wherein s is
 0. 13. Apharmaceutical composition comprising an effective amount of a compoundaccording to claim 1 and a pharmaceutically acceptable diluent orcarrier.
 14. A method of inhibiting phosphodiesterase type IV in amammal in need thereof which comprises administering to said mammal aphosphodiesterase IV inhibiting amount of a compound according toclaim
 1. 15. A method of treating an inflammatory condition in a mammalin need thereof which comprises administering to said mammal anantiinflammatory amount of a compound according to claim
 1. 16. A methodof treating AIDS, asthma, arthritis, bronchitis, chronic obstructivepulmonary disease, psoriasis, allergic rhinitis, dermatitis or shock ina mammal in need thereof which comprises administering to said mammal aneffective amount of a compound according to claim 1.